Lithium amides, for example, lithium diisopropylamide, are widely used as reagents for reactions with aldehydes and ketones in the preparation of pharmaceuticals and specialty chemicals. Lithium amides are particularly useful for the preparation of lithium acetylide compounds which are used to form acetylenic substituted organic compounds such as steroid and fragrance intermediates. In order to form the lithium acetylide, acetylene is reacted with a lithium amide, such as lithium diisopropylamide just prior to reacting the newly formed lithium acetylide with the ketone or other reagent in the same reactor. All of the steps in the prior art are performed below 0.degree.C. Usually, it is necessary to add an ether cosolvent such as tetrahydrofuran (THF) at this point to increase the limited solubility of the reagents and the subsequently formed lithium salt of the product from the reaction with the ketone. The lithium amide may be added as a preformed solution or it may be formed in the same reactor by reacting an alkyllithium such as n-butyllithium with an amine such as diisopropyl amine. In either case, the lithium amide usually exhibits lower solubility than desired for maximum reactivity and yet there is a need to minimize the amount of solvents employed.
In order to increase the concentration of the lithium amide in the preformed solutions, ethers such as tetrahydrofuran and/or complexing agents such as organomagnesium compounds, which are also stabilizing agents, have been added to increase the solubility of the lithium amide in solution. The presence of the ethers makes these solutions unstable and they decompose on standing in storage. The presence of magnesium compounds in the reaction and subsequent workup is undesirable because the possibility of lower reactivity and yields of desired products plus the more difficult workup due to the presence of the formed magnesium oxide and hydroxide which are highly insoluble and formed during washing.
Additionally, when tetrahydrofuran is used as the solvent it has been found necessary to limit the amount of tetrahydrofuran to no more than one mole for each mole of lithium amide in order to minimize degradation of the system. This also produces problems in recovering mixed solvents.
Aromatic solvents were not utilized as the solvent for preparing preformed lithium amide solutions in the past because the increased solubility was not appreciated and the belief that there would result a degradation of the organo lithium in an aromatic solution. It has been found that mixed amines provide higher solubilities in alyshatis solvents.
Monolithium acetylide is a valuable reagent for the preparation of ethynyl carbinols and terminal acetylenes. Monolithium acetylide has been used to ethynylate 17-keto steroids unsubstituted in the C.sub.16 position. However, it was previously necessary to utilize only tetrahydrofuran (THF) or other ethereal solvents to prepare the reagent. Such solvents cause problems in commercial scale processes.
It is well known to prepare 17-keto, 3-keto or 3, 17-diketo steroids with substituents on the A, B or C rings, see for example U.S. Pat. Nos. 3,166,551; 3,065,146; 3,516,991; 3,629,298 and 4,216,159.
M. M. Midland in J. Org. Chem. 40, 2250 (1975) reported reacting n-butyllithium with acetylene in THF at low temperatures (&lt;-70.degree. C.) and in dilute solutions to produce monolithium acetylide. (See Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, Wiley, New York, 1967, p. 573). Midland found that warming or attempting to generate a more concentrated solution resulted in disproportionation to the insoluble dilithium acetylide and acetylene. This disproportionation is an important disadvantage and occurs in the absence of a complexing agent. (See Corbellini et al, Chem. Ind. (Milan) 42, 251 (1960) and Chem. Abstr. 54, 19250 (1960)). To reduce or prevent the disproportionation, the monolithium acetylide is usually prepared in liquid ammonia, which presumably services as an appropriate complexing agent. An amine such as ethylenediamine can also be used to stabilize monolithium acetylide. Ethylenediamine, while stabilizing monolithium acetylide to the point it can be sold commercially, actually reduces the reactivity of the reagent to the point that it is not useful for many ethynylation procedures.
U.S. Pat. No. 4,005,562 discloses the use of monolithium acetylide to ethynylate 17-keto steroids unsubstituted in the C.sub.16 position. The monolithium acetylide was prepared by bubbling acetylene into THF held at -70.degree. C. under anhydrous conditions followed by addition of butyllithium. The 17-keto steroid was added to the unstabilized monolithium acetylide and the mixture stirred for 3 hours at -70.degree. C. to produce the 17.alpha.-ethynyl-17.beta.-hydroxy steroid product.
U.S. Pat. No. 4,320,236 discloses the use of a monolithium acetylide-ammonium complex (which is well known to those skilled in the art) to ethynylate ketones at below about -30.degree. C. The examples in U.S. Pat. No. 4,320,236 disclose ethynylation reaction temperatures of -50.degree. to 10.degree. C. The unsaturated acyclic ketones ethynylated in U.S. Pat. No. 4,320,236 are very reactive whereas the monolithium acetylide reagent produced by the process of the present invention is reactive with steroidal 17-ketones such as cyclopentanones, that are ordinarily much less reactive.
U.S. Pat. No. 4,526,720 to Van Rheenen et al discloses a one pot and a two pot process for preparing monolithium acetylide. Each reaction involves contacting an organolithium compound with a solution containing acetylene in the presence of a stabilizing amine. The amine reacts with the organolithium compound to form a lithium complex and/or a corresponding lithium amide which is subsequently reacted with acetylene.
U.S. Pat. No. 4,595,779 to Morrison et al relates to a composition and method for preparing lithium diisopropylamide by the reaction of lithium metal and diisopropylamine in tetrahydrofuran and an inert liquid hydrocarbon cosolvent including styrene as an electron carrier. However, the use of tetrahydrofuran is considered essential in the preparation when utilizing lithium metal.
The article of Keith Smith entitled "Lithiation and Organic Synthesis", Chemistry In Britain. Jan. 1982, pages 29-32, discloses the preparation of lithium dialkyl amides for use as lithiating agents by the reaction of organolithium reagents in aliphatic hydrocarbon solvents.
U.S. Pat. No. 3,542,512 to Honeycutt relates to the preparation of lithium amide by contacting lithium metal with liquid ammonia and then heating the mixture at a temperature about 150.degree. degrees C. in an inert liquid medium. The inert liquid medium includes aromatic compounds having a boiling point above 200 degrees C.
It is an object of the present invention to provide novel lithium cycloalkylimides reagent compositions having greater amounts of the lithium cycloalkylimides in solution.
It is a further object of the invention to provide a process for preparing lithium cycloalkylimides in higher concentrations in solution and in a solvent which is stable.
It is a yet still further object of the invention to prepare lithium cycloalkylimides in situ to utilize the resulting mixture to prepare lithium acetylide and optionally carry on further reactions with aldehydes or ketones.
It is still another object of the invention to prepare novel lithium cyclohexamethylenimine and reagent compositions thereof.
It is yet another object of the invention to provide a novel mixture of lithium compounds for use in a reagent composition for the preparation of lithium acetylide in high yields.